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Brockow K, Bent RK, Schneider S, Spies S, Kranen K, Hindelang B, Kurgyis Z, Broesby-Olsen S, Biedermann T, Grattan CE. Challenges in the Diagnosis of Cutaneous Mastocytosis. Diagnostics (Basel) 2024; 14:161. [PMID: 38248039 PMCID: PMC10814739 DOI: 10.3390/diagnostics14020161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/19/2023] [Accepted: 01/02/2024] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND Mastocytosis is characterized by an accumulation of clonal mast cells (MCs) in tissues such as the skin. Skin lesions in mastocytosis may be clinically subtle or heterogeneous, and giving the correct diagnosis can be difficult. METHODS This study compiles personal experiences together with relevant literature, discussing possible obstacles encountered in diagnosing skin involvement in mastocytosis and cutaneous mastocytosis (CM). RESULTS The nomenclature of the term "CM" is ambiguous. The WHO classification defines CM as mastocytosis solely present in the skin. However, the term is also used as a morphological description, e.g., in maculopapular cutaneous mastocytosis (MPCM). This is often seen in systemic, as well as cutaneous, mastocytosis. Typical CM manifestations (MPCM), including mastocytoma or diffuse cutaneous mastocytosis (DCM), all share a positive Darier's sign, and can thus be clinically recognized. Nevertheless, distinguishing monomorphic versus polymorphic MPCM may be challenging, even for experienced dermatologists. Less typical clinical presentations, such as MPCM with telangiectatic erythemas (formerly called telangiectasia macularis eruptiva perstans), confluent, nodular or xanthelasmoid variants may require a skin biopsy for histopathological confirmation. Because MC numbers in CM have a large overlap to those in healthy and inflamed skin, detailed histopathological criteria to diagnose mastocytosis in MPCM are needed and have been proposed. D816V KIT mutational analysis in tissue is helpful for confirming the diagnosis. Biomarkers allow the prediction of the course of CM into regression or evolution of the disease. Further diagnostic measures should screen for concomitant diseases, such as malignant melanoma, and for systemic involvement. CONCLUSIONS Whereas in typical cases the diagnosis of CM may be uncomplicated, less typical manifestations may require specific investigations for making the diagnosis and predicting its course.
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Affiliation(s)
- Knut Brockow
- Department of Dermatology and Allergy Biederstein, School of Medicine and Health, Technical University of Munich, 80802 Munich, Germany (T.B.)
- Department of Dermatology and Allergy Centre, Odense University Hospital, 5000 Odense, Denmark
| | - Rebekka Karolin Bent
- Department of Dermatology and Allergy Biederstein, School of Medicine and Health, Technical University of Munich, 80802 Munich, Germany (T.B.)
| | - Simon Schneider
- Department of Dermatology and Allergy Biederstein, School of Medicine and Health, Technical University of Munich, 80802 Munich, Germany (T.B.)
| | - Sophie Spies
- Department of Dermatology and Allergy Biederstein, School of Medicine and Health, Technical University of Munich, 80802 Munich, Germany (T.B.)
| | - Katja Kranen
- Department of Dermatology and Allergy Biederstein, School of Medicine and Health, Technical University of Munich, 80802 Munich, Germany (T.B.)
| | - Benedikt Hindelang
- Department of Dermatology and Allergy Biederstein, School of Medicine and Health, Technical University of Munich, 80802 Munich, Germany (T.B.)
| | - Zsuzsanna Kurgyis
- Department of Dermatology and Allergy Biederstein, School of Medicine and Health, Technical University of Munich, 80802 Munich, Germany (T.B.)
| | - Sigurd Broesby-Olsen
- Department of Dermatology and Allergy Centre, Odense University Hospital, 5000 Odense, Denmark
| | - Tilo Biedermann
- Department of Dermatology and Allergy Biederstein, School of Medicine and Health, Technical University of Munich, 80802 Munich, Germany (T.B.)
| | - Clive E. Grattan
- St John’s Institute of Dermatology, Guy’s Hospital, London SE1 9RT, UK
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Costa A, Scalzulli E, Carmosino I, Capriata M, Ielo C, Masucci C, Passucci M, Martelli M, Breccia M. Systemic mastocytosis: 2023 update on diagnosis and management in adults. Expert Opin Emerg Drugs 2023; 28:153-165. [PMID: 37256917 DOI: 10.1080/14728214.2023.2221028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 05/27/2023] [Accepted: 05/30/2023] [Indexed: 06/02/2023]
Abstract
INTRODUCTION Systemic mastocytosis (SM) is a complex and heterogeneous disease, characterized by the clonal accumulation of mast cells in one or more organs. In 2022 both the World Health Organization (WHO) and the International Consensus Classification (ICC) modified the diagnostic and classification criteria of SM. Moreover, the identification of new clinical and molecular variables has improved prognostic tools and led to increasingly individualized therapeutic strategies. AREAS COVERED The aim of this review is to present the updates introduced by the International Consensus Classification in diagnostic criteria of SM. In addition, we report the latest data available from the most important clinical trials in patients both with non-advanced and advanced disease, including elenestinib and bezuclastinib. EXPERT OPINION Diagnosis and classification of SM has evolved over years. The most recent WHO and ICC classification improved SM diagnostic work-up, providing clinicians with a clear and simplified diagnostic scheme. New approved targeted therapies such as midostaurin and avapritinib modified the treatment paradigm in patients in advanced stage, and next-generation inhibitors actually investigated in clinical trials are expected in the next future.
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Affiliation(s)
- Alessandro Costa
- Hematology Unit, Businco Hospital, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Emilia Scalzulli
- Hematology, Department of Translational and Precision Medicine, Az. Policlinico Umberto I-Sapienza University, Rome, Italy
| | - Ida Carmosino
- Hematology, Department of Translational and Precision Medicine, Az. Policlinico Umberto I-Sapienza University, Rome, Italy
| | - Marcello Capriata
- Hematology, Department of Translational and Precision Medicine, Az. Policlinico Umberto I-Sapienza University, Rome, Italy
| | - Claudia Ielo
- Hematology, Department of Translational and Precision Medicine, Az. Policlinico Umberto I-Sapienza University, Rome, Italy
| | - Chiara Masucci
- Hematology, Department of Translational and Precision Medicine, Az. Policlinico Umberto I-Sapienza University, Rome, Italy
| | - Mauro Passucci
- Hematology, Department of Translational and Precision Medicine, Az. Policlinico Umberto I-Sapienza University, Rome, Italy
| | - Maurizio Martelli
- Hematology, Department of Translational and Precision Medicine, Az. Policlinico Umberto I-Sapienza University, Rome, Italy
| | - Massimo Breccia
- Hematology, Department of Translational and Precision Medicine, Az. Policlinico Umberto I-Sapienza University, Rome, Italy
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Pardanani A. Systemic mastocytosis in adults: 2023 update on diagnosis, risk stratification and management. Am J Hematol 2023; 98:1097-1116. [PMID: 37309222 DOI: 10.1002/ajh.26962] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 04/29/2023] [Accepted: 05/02/2023] [Indexed: 06/14/2023]
Abstract
OVERVIEW Systemic mastocytosis (SM) results from clonal proliferation of mast cells (MC) in extracutaneous organs. DIAGNOSIS The major criterion is presence of multifocal MC clusters in the bone marrow and/or extracutaneous organs. Minor diagnostic criteria include elevated serum tryptase level, MC CD25/CD2/CD30 expression, and presence of activating KIT mutations. RISK STRATIFICATION Establishing SM subtype as per the International Consensus Classification/World Health Organization classification systems is an important first step. Patients either have indolent/smoldering SM (ISM/SSM) or advanced SM, including aggressive SM (ASM), SM with associated myeloid neoplasm (SM-AMN), and mast cell leukemia. Identification of poor-risk mutations (i.e., ASXL1, RUNX1, SRSF2, NRAS) further refines the risk stratification. Several risk models are available to help assign prognosis in SM patients. MANAGEMENT Treatment goals for ISM patients are primarily directed toward anaphylaxis prevention/symptom control/osteoporosis treatment. Patients with advanced SM frequently need MC cytoreductive therapy to reverse disease-related organ dysfunction. Tyrosine kinase inhibitors (TKI) (midostaurin, avapritinib) have changed the treatment landscape in SM. While deep biochemical, histological and molecular responses have been documented with avapritinib treatment, its efficacy as monotherapy against a multimutated AMN disease component in SM-AMN patients remains unclear. Cladribine continues to have a role for MC debulking, whereas interferon-α has a diminishing role in the TKI era. Treatment of SM-AMN primarily targets the AMN component, particularly if an aggressive disease such as acute leukemia is present. Allogeneic stem cell transplant has a role in such patients. Imatinib has a therapeutic role only in the rare patient with an imatinib-sensitive KIT mutation.
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Affiliation(s)
- Animesh Pardanani
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
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Zhang X, Han J, Zhu N, Ji Y, Hou Y. Systemic mastocytosis mimicking blastic plasmacytoid dendritic cell neoplasm: a case report. Diagn Pathol 2023; 18:17. [PMID: 36759849 PMCID: PMC9912652 DOI: 10.1186/s13000-023-01301-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 01/19/2023] [Indexed: 02/11/2023] Open
Abstract
BACKGROUND Systemic mastocytosis (SM), a rare myeloid neoplasm, is defined as a clonal and neoplastic proliferation of mast cells in at least one extracutaneous organ(s). The pathologic diagnosis and treatment of SM are challenging. CASE PRESENTATION We presented a 44-year-old male patient who had endured abdomen discomfort for 4 years and diarrhea for 5 months. Colonoscopy and PET/CT found a protuberant lesion in the cecum with adjacent lymphadenopathy. Histopathology of the cecum biopsy showed diffuse infiltration of medium-sized round/oval cells in lamina propria with immunohistochemical expressions of CD45, CD117, CD25, CD68, CD123, CD56, CD4, and CD35, mimicking blastic plasmacytoid dendritic cell neoplasm. Sanger sequencing revealed missense mutation (D816V) in the exon 17 of KIT gene. Serum tryptase level was 38.56 ng/ml. No abnormality was found in skin examination and bone marrow biopsy. No primitive cells were observed in bone marrow smear and peripheral blood smear. The diagnosis of aggressive SM with intestinal tract involvement was established. The patient received avapritinib treatment at an initial dosage of 200 mg once daily and exhibited dramatic clinical improvement but memory impairment within 1 month. No recurrence was observed in 1-year follow-up at the adjusted avapritinib dose (75 mg once daily). CONCLUSIONS SM is very rare and should be considered in patients with long-term diarrhea symptoms and hematopoietic/lymphoid-appearing tumors. KIT D816V mutation contributes to the differentiation of CD123, CD4, and CD56 immunoreactive SM from blastic plasmacytoid dendritic cell neoplasm. The rare side-effect of memory impairment in this case helps to accumulate the experience of avapritinib in treating KIT D816V-mutant SM.
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Affiliation(s)
- Xin Zhang
- grid.8547.e0000 0001 0125 2443Department of Pathology, Fudan University Zhongshan Hospital, 180 Fenglin Road, Shanghai, 200032 China
| | - Jing Han
- grid.8547.e0000 0001 0125 2443Department of Pathology, Fudan University Zhongshan Hospital, 180 Fenglin Road, Shanghai, 200032 China
| | - Na Zhu
- grid.8547.e0000 0001 0125 2443Department of Pathology, Fudan University Zhongshan Hospital, 180 Fenglin Road, Shanghai, 200032 China
| | - Yuan Ji
- grid.8547.e0000 0001 0125 2443Department of Pathology, Fudan University Zhongshan Hospital, 180 Fenglin Road, Shanghai, 200032 China
| | - Yingyong Hou
- Department of Pathology, Fudan University Zhongshan Hospital, 180 Fenglin Road, Shanghai, 200032, China.
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Crupi F, Sordi B, Vanderwert F, Gesullo F, Amorosi A, Mannelli F, Santi R. Histopathology and Molecular Genetics in Systemic Mastocytosis: Implications for Clinical Management. Int J Mol Sci 2022; 23:ijms23158772. [PMID: 35955907 PMCID: PMC9369381 DOI: 10.3390/ijms23158772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 07/21/2022] [Accepted: 08/03/2022] [Indexed: 11/16/2022] Open
Abstract
The diagnosis of systemic mastocytosis (SM) is based on various clinical, dermatological, serological, and hematological findings but essentially relies on histological evidence of an abnormal increase in tissue-localized mast cells (MCs). The extra-cutaneous organ most frequently affected is the bone marrow (BM), and therefore, histological examination of trephine biopsy specimens of the iliac crest is mandatory on suspicion of SM. At microscopic examination, neoplastic MCs show aberrant morphology, usually with prominent spindling. Immunohistochemistry is a useful tool in the diagnosis of SM because mast cell (MC) infiltrates may be slight and scarce, in a mixed background of lymphohistiocytic cells, eosinophils, and plasma cells. Moreover, neoplastic MCs exhibit an aberrant phenotype. Recent evidence, largely derived from molecular genetics, has enhanced the diagnostic capability of SM, also providing the basis for adequate prognostic and therapeutic evaluation. The cases herein reported illustrate the variable clinical manifestations and disease course of SM, focusing on diagnostic and therapeutic challenges. In accordance with the World Health Organization (WHO) classification and the International Consensus Classification (ICC) systems, our findings emphasize the importance of an integrated diagnostic approach for SM, with proper application of diverse assessment methodologies in order to improve SM classification and treatment effectiveness.
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Affiliation(s)
- Francesca Crupi
- Centro Ricerca e Innovazione Malattie Mieloproliferative (CRIMM), AOU Careggi, 50134 Firenze, Italy
| | - Benedetta Sordi
- Centro Ricerca e Innovazione Malattie Mieloproliferative (CRIMM), AOU Careggi, 50134 Firenze, Italy
| | - Fiorenza Vanderwert
- Centro Ricerca e Innovazione Malattie Mieloproliferative (CRIMM), AOU Careggi, 50134 Firenze, Italy
| | - Francesca Gesullo
- Centro Ricerca e Innovazione Malattie Mieloproliferative (CRIMM), AOU Careggi, 50134 Firenze, Italy
| | - Andrea Amorosi
- Dipartimento di Scienze della Salute, Università Magna Grecia, 88100 Catanzaro, Italy
| | - Francesco Mannelli
- Centro Ricerca e Innovazione Malattie Mieloproliferative (CRIMM), AOU Careggi, 50134 Firenze, Italy
| | - Raffaella Santi
- Sezione di Anatomia Patologica, Dipartimento di Scienze della Salute, Università degli Studi di Firenze, 50121 Firenze, Italy
- Correspondence:
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6
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Pardanani A. Systemic mastocytosis in adults: 2021 Update on diagnosis, risk stratification and management. Am J Hematol 2021; 96:508-525. [PMID: 33524167 DOI: 10.1002/ajh.26118] [Citation(s) in RCA: 104] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 01/08/2021] [Indexed: 12/16/2022]
Abstract
OVERVIEW Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in extra-cutaneous organs. DIAGNOSIS The major criterion is presence of multifocal clusters of spindled MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC CD25 expression, and presence of KITD816V mutation. RISK STRATIFICATION Establishing SM subtype as per the World Health Organization classification system is an important first step. Broadly, patients either have indolent/smoldering SM (ISM/SSM) or advanced SM, the latter includes aggressive SM (ASM), SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL). Identification of poor-risk mutations (ie, ASXL1, RUNX1, SRSF2, NRAS) further refines the risk stratification. Recently, clinical and hybrid clinical-molecular risk models have been developed to more accurately assign prognosis in SM patients. MANAGEMENT Treatment goals for ISM patients are primarily directed towards anaphylaxis prevention/symptom control/osteoporosis treatment. Patients with advanced SM frequently need MC cytoreductive therapy to ameliorate disease-related organ dysfunction. High response rates have been seen with small-molecule inhibitors that target mutant-KIT, including midostaurin (Food and Drug Administration approved) or avapritinib (investigational). Other options for MC cytoreduction include cladribine or interferon-α, although head-to-head comparisons are lacking. Treatment of SM-AHN primarily targets the AHN component, particularly if an aggressive disease such as acute myeloid leukemia is present. Allogeneic stem cell transplant can be considered in such patients, or in those with relapsed/refractory advanced SM. Imatinib has a limited therapeutic role in SM; effective cytoreduction is limited to those with imatinib-sensitive KIT mutations.
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Affiliation(s)
- Animesh Pardanani
- Division of Hematology, Department of Medicine Mayo Clinic Rochester Minnesota
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Craig JW, Hasserjian RP, Kim AS, Aster JC, Pinkus GS, Hornick JL, Steensma DP, Coleman Lindsley R, DeAngelo DJ, Morgan EA. Detection of the KIT D816V mutation in myelodysplastic and/or myeloproliferative neoplasms and acute myeloid leukemia with myelodysplasia-related changes predicts concurrent systemic mastocytosis. Mod Pathol 2020; 33:1135-1145. [PMID: 31896808 DOI: 10.1038/s41379-019-0447-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/16/2019] [Accepted: 12/16/2019] [Indexed: 12/20/2022]
Abstract
Greater than 90% of cases of systemic mastocytosis (SM) harbor pathogenic KIT mutations, particularly KITD816V. Prognostically-significant pathogenic KIT mutations also occur in 30-40% of core binding factor-associated acute myeloid leukemia (CBF-AML), but are uncommonly associated with concurrent SM. By comparison, the occurrence of SM in other myeloid neoplasms bearing pathogenic KIT mutations, particularly those with a chronic course, is poorly understood. Review of clinical next-generation sequencing (NGS) performed at our institutions in patients with known or suspected hematologic malignancies over an 8-year period revealed 64 patients with both a pathogenic KIT mutation detected at one or more timepoints and available bone marrow biopsy materials. Patients with KITD816V-mutated myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), or overlap MDS/MPN (n = 22) accounted for approximately one-third of our cohort (34%). Comprehensive morphologic and immunophenotypic characterization revealed that nearly all cases (n = 20, 91%) exhibited concurrent SM. In contrast, of the 18 patients (28%) with AML and KITD816V, only eight (44%) showed evidence of SM at any point in their disease course (p = 0.0021); of these eight, the AML component was characterized as AML with myelodysplasia-related changes (AML-MRC) in all but one instance (n = 7, 87%). Twelve patients (19%) had pathogenic KIT mutations other than p.D816V, all in the setting of AML (CFB-AML, n = 7; AML, not otherwise specified, n = 2; AML-MRC, n = 1; acute promyelocytic leukemia, n = 1); only two of these patients (17%), both with CBF-AML, exhibited concurrent SM. The remaining 12 patients (19%) had SM without evidence of an associated hematological neoplasm (AHN). For nearly one-third of the 30 SM-AHN patients in our cohort (n = 9, 30%), the SM component of their disease was not initially clinicopathologically recognized. We propose that identification of the KITD816V mutation in patients diagnosed with MDS, MPN, MDS/MPN, or AML-MRC should trigger reflex testing for SM.
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Affiliation(s)
- Jeffrey W Craig
- Department of Pathology and Laboratory Medicine, BC Cancer Agency, Vancouver, BC, Canada
| | - Robert P Hasserjian
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Annette S Kim
- Harvard Medical School, Boston, MA, USA.,Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Jon C Aster
- Harvard Medical School, Boston, MA, USA.,Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Geraldine S Pinkus
- Harvard Medical School, Boston, MA, USA.,Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Jason L Hornick
- Harvard Medical School, Boston, MA, USA.,Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - David P Steensma
- Harvard Medical School, Boston, MA, USA.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - R Coleman Lindsley
- Harvard Medical School, Boston, MA, USA.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Daniel J DeAngelo
- Harvard Medical School, Boston, MA, USA.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Elizabeth A Morgan
- Harvard Medical School, Boston, MA, USA. .,Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
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Metcalfe DD, Mekori YA. Pathogenesis and Pathology of Mastocytosis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2017; 12:487-514. [PMID: 28135563 DOI: 10.1146/annurev-pathol-052016-100312] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Systemic mastocytosis is a clonal disorder of mast cells that may variably present with characteristic skin lesions, episodes of mast cell mediator release, and disturbances of hematopoiesis. No curative therapy presently exists. Conventional management has relied on agents that antagonize mediators released by mast cells, inhibit mediator secretion, or modulate mast cell proliferation. Recent advances in the molecular understanding of the pathophysiology of systemic mastocytosis have provided new therapeutic considerations, including new and novel tyrosine kinase inhibitors.
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Affiliation(s)
- Dean D Metcalfe
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892;
| | - Yoseph A Mekori
- Tel Hai College, Upper Galilee, 1220800 Israel; .,Meir Medical Center, Kfar Saba 44281, Israel.,Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
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9
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Pardanani A. Systemic mastocytosis in adults: 2017 update on diagnosis, risk stratification and management. Am J Hematol 2016; 91:1146-1159. [PMID: 27762455 DOI: 10.1002/ajh.24553] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 09/12/2016] [Indexed: 12/17/2022]
Abstract
Disease overview:Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extra-cutaneous organs. DIAGNOSIS The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. Risk stratification: The 2008 World Health Organization (WHO) classification of SM has been shown to be prognostically relevant. Classification of SM patients into indolent (SM), aggressive SM (ASM), SM associated with a clonal non-MC lineage disease (SM-AHNMD) and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis. MANAGEMENT SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom-directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease-related organ dysfunction; interferon-α (±corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal and mediator-release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib-sensitive KIT mutation or in KITD816-unmutated patients. Treatment of SM-AHNMD is governed primarily by the non-MC neoplasm; hydroxyurea has modest utility in this setting; there is a role for allogeneic stem cell transplantation in select cases. Investigational drugs: Recent data confirms midostaurin's significant anti-MC activity in patients with advanced SM. Am. J. Hematol. 91:1147-1159, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Animesh Pardanani
- Division of Hematology Department of Medicine; Mayo Clinic; Rochester Minnesota
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Ustun C, Gotlib J, Popat U, Artz A, Litzow M, Reiter A, Nakamura R, Kluin-Nelemans HC, Verstovsek S, Gajewski J, Perales MA, George T, Shore T, Sperr W, Saber W, Kota V, Yavuz AS, Pullarkat V, Rogosheske J, Hogan W, Van Besien K, Hagglund H, Damaj G, Arock M, Horny HP, Metcalfe DD, Deeg HJ, Devine S, Weisdorf D, Akin C, Valent P. Consensus Opinion on Allogeneic Hematopoietic Cell Transplantation in Advanced Systemic Mastocytosis. Biol Blood Marrow Transplant 2016; 22:1348-1356. [PMID: 27131865 DOI: 10.1016/j.bbmt.2016.04.018] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Accepted: 04/20/2016] [Indexed: 12/16/2022]
Affiliation(s)
- Celalettin Ustun
- Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota.
| | - Jason Gotlib
- Division of Hematology, Stanford University, Stanford, California
| | - Uday Popat
- Department of Stem Cell Transplantation, University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - Andrew Artz
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Mark Litzow
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Minneapolis, Minnesota
| | - Andreas Reiter
- Department of Hematology and Oncology, University Medical Centre Mannheim, Mannheim, Germany
| | - Ryotaro Nakamura
- Department of Hematology/Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, California
| | - Hanneke C Kluin-Nelemans
- Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Srdan Verstovsek
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - James Gajewski
- Department of Hematology, Oregon Health and Science University, Portland, Oregon
| | - Miguel-Angel Perales
- Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Tracy George
- Department of Pathology, University of New Mexico, Albuquerque, New Mexico
| | - Tsiporah Shore
- Division of Hematology and Oncology, Weill Cornell Medical College, New York, New York
| | - Wolfgang Sperr
- Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria
| | - Wael Saber
- Department of Medicine, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Vamsi Kota
- Division of Hematology, Department of Hematology and Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia
| | - Akif Selim Yavuz
- Division of Hematology, Istanbul Medical School, University of Istanbul, Istanbul, Turkey
| | - Vinod Pullarkat
- Department of Hematology/Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, California
| | - John Rogosheske
- Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota
| | - William Hogan
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Minneapolis, Minnesota
| | - Koen Van Besien
- Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Hans Hagglund
- Division of Hematology, Department of Medical Sciences Uppsala University, Uppsala, Sweden
| | - Gandhi Damaj
- Department of Hematology, Hematology Institute, University Hospital, School of Medicine, University of Basse-Normandie, Caen, France
| | - Michel Arock
- Cellular and Molecular Oncology Unit, CNRS UMR 8113, Ecole Normale Supériede Cachan, Cachan, France and Laboratoire d'Hématologie, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France
| | | | - Dean D Metcalfe
- Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - H Joachim Deeg
- Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, University of Washington, Seattle, Washington
| | - Steven Devine
- Division of Hematology, Department of Medicine, Ohio State University and the Ohio State University Comprehensive Cancer Center, Ohio
| | - Daniel Weisdorf
- Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota
| | - Cem Akin
- Division of Rheumatology, Immunology, and Allergy, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts
| | - Peter Valent
- Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria
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Lieberman P, Nicklas RA, Randolph C, Oppenheimer J, Bernstein D, Bernstein J, Ellis A, Golden DBK, Greenberger P, Kemp S, Khan D, Ledford D, Lieberman J, Metcalfe D, Nowak-Wegrzyn A, Sicherer S, Wallace D, Blessing-Moore J, Lang D, Portnoy JM, Schuller D, Spector S, Tilles SA. Anaphylaxis--a practice parameter update 2015. Ann Allergy Asthma Immunol 2016; 115:341-84. [PMID: 26505932 DOI: 10.1016/j.anai.2015.07.019] [Citation(s) in RCA: 314] [Impact Index Per Article: 34.9] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 07/12/2015] [Indexed: 12/12/2022]
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12
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Cytokine Regulation of Microenvironmental Cells in Myeloproliferative Neoplasms. Mediators Inflamm 2015; 2015:869242. [PMID: 26543328 PMCID: PMC4620237 DOI: 10.1155/2015/869242] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 08/13/2015] [Indexed: 12/13/2022] Open
Abstract
The term myeloproliferative neoplasms (MPN) refers to a heterogeneous group of diseases including not only polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), but also chronic myeloid leukemia (CML), and systemic mastocytosis (SM). Despite the clinical and biological differences between these diseases, common pathophysiological mechanisms have been identified in MPN. First, aberrant tyrosine kinase signaling due to somatic mutations in certain driver genes is common to these MPN. Second, alterations of the bone marrow microenvironment are found in all MPN types and have been implicated in the pathogenesis of the diseases. Finally, elevated levels of proinflammatory and microenvironment-regulating cytokines are commonly found in all MPN-variants. In this paper, we review the effects of MPN-related oncogenes on cytokine expression and release and describe common as well as distinct pathogenetic mechanisms underlying microenvironmental changes in various MPN. Furthermore, targeting of the microenvironment in MPN is discussed. Such novel therapies may enhance the efficacy and may overcome resistance to established tyrosine kinase inhibitor treatment in these patients. Nevertheless, additional basic studies on the complex interplay of neoplastic and stromal cells are required in order to optimize targeting strategies and to translate these concepts into clinical application.
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13
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Reichard KK, Chen D, Pardanani A, McClure RF, Howard MT, Kurtin PJ, Wood AJ, Ketterling RP, King RL, He R, Morice WG, Hanson CA. Morphologically occult systemic mastocytosis in bone marrow: clinicopathologic features and an algorithmic approach to diagnosis. Am J Clin Pathol 2015; 144:493-502. [PMID: 26276780 DOI: 10.1309/ajcpsgq71gjqqacl] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVES Bone marrow (BM) biopsy specimens involved by systemic mastocytosis (SM) typically show multifocal, compact, dense aggregates of spindled mast cells (MCs). However, some cases lack aggregate formation and fulfill the World Health Organization 2008 criteria for SM, based on minor criteria. METHODS We identified 26 BM cases of KIT D816V-mutated, morphologically occult SM in the BM. RESULTS All patients had some combination of allergic/MC activating symptoms. Peripheral blood counts were generally normal. BM aspirates showed 5% or less MCs, which were only occasionally spindled. BM biopsy specimens showed no morphologic classic MC lesions. Tryptase immunohistochemistry (IHC) demonstrated interstitial, individually distributed MCs (up to 5%) with prominent spindling, lacking aggregate formation. MCs coexpressed CD25 by IHC and/or flow cytometry. Spindled MCs constituted more than 25% of total MCs in all cases and more than 50% in 20 of 26 cases. CONCLUSIONS Morphologically occult involvement of normal-appearing BM by SM will be missed without appropriate clinical suspicion and pathologic evaluation by tryptase and CD25 IHC and KIT D816V mutation analysis. On the basis of these findings, we propose a cost-effective, data-driven, evidence-based algorithmic approach to the workup of these cases.
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Affiliation(s)
| | | | | | - Rebecca F. McClure
- Division of Hematopathology, Health Sciences North, Sudbury, Ontario, Canada
| | | | | | | | | | | | - Rong He
- Divisions of Hematopathology,
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14
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Systemic Mastocytosis: Clinical Update and Future Directions. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2015; 15:728-38. [PMID: 26382091 DOI: 10.1016/j.clml.2015.07.644] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Revised: 07/13/2015] [Accepted: 07/28/2015] [Indexed: 12/20/2022]
Abstract
Systemic mastocytosis (SM) is defined as the accumulation of abnormal mast cells (MC) in 1 or more extracutaneous tissues. Symptoms are due to either MC activation or organ infiltration and vary depending on disease subtype. More benign forms of SM, such as indolent SM, result in a life expectancy similar to the general population, while more aggressive subtypes, such as MC leukemia (MCL), have a median survival measured on the order of months. Treatment of indolent SM is directed at controlling the symptoms associated with MC activation. In advanced forms, such as aggressive SM and MCL, agents targeting MC proliferation such as KIT tyrosine kinase inhibitors, cladribine, and thalidomide may be provided. Newer agents based on preclinical rationale are also being actively investigated. However, the only potentially curative therapy for aggressive SM/MCL remains hematopoietic stem cell transplantation. Given that SM is a relatively rare disease, clinicians are often underprepared to evaluate, diagnose, and effectively treat this clinically heterogeneous condition. Here we seek to familiarize clinicians with this orphan disease and review current and future treatment approaches.
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15
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Pardanani A. Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management. Am J Hematol 2015; 90:250-62. [PMID: 25688753 DOI: 10.1002/ajh.23931] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 12/24/2014] [Indexed: 12/20/2022]
Abstract
DISEASE OVERVIEW Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extracutaneous organs. DIAGNOSIS The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. RISK STRATIFICATION The 2008 World Health Organization classification of SM has been shown to be prognostically relevant. Classification of SM patients into indolent SM (ISM), aggressive SM (ASM), SM associated with a clonal non-MC lineage disease (SM-AHNMD), and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis. MANAGEMENT SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom-directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease-related organ dysfunction; interferon-α (+/-corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator-release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib-sensitive KIT mutation or in KITD816-unmutated patients. Treatment of SM-AHNMD is governed primarily by the non-MC neoplasm; hydroxyurea has modest utility in this setting; there is a role for allogeneic stem cell transplantation in select cases. Investigational Drugs: Recent data confirms midostaurin's significant anti-MC activity in patients with advanced SM.
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Affiliation(s)
- Animesh Pardanani
- Division of Hematology; Mayo Clinic; Rochester Minnesota
- Department of Medicine; Mayo Clinic; Rochester Minnesota
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Abstract
SUMMARY Mast cell leukemia (MCL) is a rare subtype of systemic mastocytosis. In MCL the numbers of mast cells exceed 19% of nucleated cells in bone marrow and/or 10% of circulating leukocytes in peripheral blood. Primary MCL must be distinguished from secondary MCL evolving from another subvariant of systemic mastocytosis or from mast cell sarcoma. Acute MCL with a poor prognosis is distinguished from the more indolent chronic MCL. Serum tryptase is significantly elevated in almost all MCL patients and activating point mutations at codon 816 of KIT (usually KIT D816V) are encountered in about 70%. Regarding differential diagnosis, other ‘tryptase-positive’ or ‘metachromatic’ leukemias must be considered, including myelomastocytic leukemia and tryptase-positive acute myeloid leukemia but also acute and chronic basophilic leukemias.
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Affiliation(s)
- Hans-Peter Horny
- Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany
| | - Andreas Reiter
- III Medical Clinic, University Hospital Mannheim, Germany
| | - Karl Sotlar
- Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany
| | - Peter Valent
- Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria
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Ranieri G, Marech I, Pantaleo M, Piccinno M, Roncetti M, Mutinati M, Rizzo A, Gadaleta CD, Introna M, Patruno R, Sciorsci RL. In vivo model for mastocytosis: A comparative review. Crit Rev Oncol Hematol 2014; 93:159-69. [PMID: 25465741 DOI: 10.1016/j.critrevonc.2014.10.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2014] [Revised: 10/01/2014] [Accepted: 10/22/2014] [Indexed: 12/27/2022] Open
Abstract
Human mastocytosis are heterogeneous group of neoplastic diseases characterized by a different degree of uncontrolled mast cell (MC) proliferation and activation. Interestingly, human mastocytosis share several biological and clinical features with canine mast cell disorders, so called canine mast cell tumors (CMCTs). These CMCTs are the most common spontaneous cutaneous tumors found in dogs representing a valid model to study neoplastic mast cell disorders. It has been discovered that the pathological activation of c-Kit receptor (c-KitR), expressed by MCs, has been involved in the pathogenesis of neoplastic MC disorders. In this review we have focused on human mastocytosis in terms of: (i) epidemiology and classification; (ii) pathogenesis at molecular levels; (iii) clinical presentation. In addition, we have summarized animal models useful to study neoplastic MC disorders including CMCTs and murine transgenic models. Finally, we have revised therapeutic approaches mostly common in human and canine MCTs and novel tyrosine kinase inhibitors approved for CMCTs and recently translated in human clinical trials.
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Affiliation(s)
- Girolamo Ranieri
- Diagnostic and Interventional Radiology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre Istituto Tumori "Giovanni Paolo II", Bari, Italy.
| | - Ilaria Marech
- Diagnostic and Interventional Radiology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Marianna Pantaleo
- Department of Emergency and Organ Transplantation (D.E.T.O.), Veterinary Medical School, Università "Aldo Moro", Bari, Italy
| | - Mariagrazia Piccinno
- Department of Emergency and Organ Transplantation (D.E.T.O.), Veterinary Medical School, Università "Aldo Moro", Bari, Italy
| | - Maria Roncetti
- Department of Emergency and Organ Transplantation (D.E.T.O.), Veterinary Medical School, Università "Aldo Moro", Bari, Italy
| | - Maddalena Mutinati
- Department of Emergency and Organ Transplantation (D.E.T.O.), Veterinary Medical School, Università "Aldo Moro", Bari, Italy
| | - Annalisa Rizzo
- Department of Emergency and Organ Transplantation (D.E.T.O.), Veterinary Medical School, Università "Aldo Moro", Bari, Italy
| | - Cosmo Damiano Gadaleta
- Diagnostic and Interventional Radiology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Marcello Introna
- Department of Pathology, Veterinary Medical School, Università "Aldo Moro", Bari, Italy
| | - Rosa Patruno
- Department of Prevention and Animal Health, ASL BAT, Barletta, Italy
| | - Raffaele Luigi Sciorsci
- Department of Emergency and Organ Transplantation (D.E.T.O.), Veterinary Medical School, Università "Aldo Moro", Bari, Italy
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18
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Pardanani A. Systemic mastocytosis in adults: 2013 update on diagnosis, risk stratification, and management. Am J Hematol 2013; 88:612-24. [PMID: 23720340 DOI: 10.1002/ajh.23459] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Accepted: 04/04/2013] [Indexed: 12/20/2022]
Abstract
DISEASE OVERVIEW Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extracutaneous organs. DIAGNOSIS The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. RISK STRATIFICATION The 2008 World Health Organization (WHO) classification of SM has been shown to be prognostically relevant. Classification of SM patients into indolent (SM), aggressive SM (ASM), SM associated with a clonal non-MC lineage disease (SM-AHNMD) and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis. MANAGEMENT SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom-directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease-related organ dysfunction; interferon-α (±corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator-release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib-sensitive KIT mutation or in KITD816-unmutated patients. Treatment of SM-AHNMD is governed primarily by the non-MC neoplasm; hydroxyurea has modest utility in this setting. INVESTIGATIONAL DRUGS Dasatinib's in vitro anti- KITD816V activity has not translated into significant therapeutic activity in most SM patients. In contrast, recently updated data confirms Midostaurin's significant anti-MC activity in patients with advanced SM.
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Affiliation(s)
- Animesh Pardanani
- Division of Hematology, Department of Medicine; Mayo Clinic; Rochester Minnesota
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Abstract
Mast cell diseases comprise a spectrum of disorders including cutaneous mastocytosis, indolent or aggressive systemic variants including leukemia, and unifocal tumor formations such as benign extracutaneous mastocytoma or aggressive mast cell sarcoma (MCS). Many mast cell diseases are associated with aberrancy of c-KIT proto-oncogene resulting in tyrosine kinase activity, typically exhibiting point mutation in codon 816. MCS is an exceedingly rare clinicopathologic entity characterized by a unifocal accumulation of neoplastic mast cells that grow in a locally destructive manner. We report a case in a 2-year-old boy who was initially diagnosed at 8 months of age with atypical cutaneous mastocytoma of the right ear with subsequent aggressive, destructive growth pattern; features that were most consistent with MCS. So far, MCS has been documented in the literature in at least 6 human cases. To the best of our knowledge, our case represents the first MCS in an infant. Thorough multimodal approach with strict follow-up is relevant in appropriately diagnosing this rare entity, particularly in differentiating this lesion from other neoplasms that are more likely to occur in infancy.
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21
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Fuller SJ. New Insights into the Pathogenesis, Diagnosis, and Management of Mastocytosis. Hematol Oncol Clin North Am 2012; 26:1143-68. [DOI: 10.1016/j.hoc.2012.08.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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22
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23
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Clinical and prognostic implications of low or high level of von Willebrand factor in patients with Waldenstrom macroglobulinemia. Blood 2012; 120:3214-21. [PMID: 22896002 DOI: 10.1182/blood-2011-11-388256] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Acquired von Willebrand syndrome is described in patients with Waldenström macroglobulinemia (WM). Assessment of ristocetin cofactor activity (VWF:RCo) and von Willebrand factor (VWF) antigen (VWF:Ag) in 72 consecutive patients with WM showed a negative relation between VWF levels < 130 U/dL and both monoclonal immunoglobulin M concentration (mIgMC) and viscosity. Ten patients with VWF:RCo < 50 U/dL (< 40 for patients with blood group O) fulfilled the acquired von Willebrand syndrome criteria. They had higher mIgMC and viscosity. Reduction in mIgMC was associated with increase in VWF levels. The low VWF:RCo/VWF:Ag ratio suggested that high viscosity might be associated with increased shear force and cleavage of multimers. Surprisingly, 43 patients (59%) presented with high VWF:Ag (> 110 U/dL). They had higher bone marrow microvessel density and vascular endothelial growth factor expression on bone marrow mast cells. Five-year survival rates of patients with VWF:Ag < 110, between 110 and 250, and more than 250 U/dL were 96%, 71%, and 44%, respectively (P < .0001). High VWF:Ag was also a significant adverse prognostic factor for survival after first-line therapy (P < .0001), independently of the international scoring system. These results support systematic assessment of VWF in patients with WM. The adverse prognostic value of high VWF levels raises issues on interactions between lymphoplasmacytic cells, mast cells, and endothelial cells in WM.
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Pardanani A. Systemic mastocytosis in adults: 2012 Update on diagnosis, risk stratification, and management. Am J Hematol 2012; 87:401-11. [PMID: 22410759 DOI: 10.1002/ajh.23134] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
DISEASE OVERVIEW Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extra-cutaneous organs. DIAGNOSIS The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. RISK STRATIFICATION The prognostic relevance of the 2008 World Health Organization (WHO) classification of SM has recently been confirmed. Classification of SM patients into indolent (SM), aggressive SM (ASM), SM associated with a clonal non-MC lineage disease (SM-AHNMD) and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis. MANAGEMENT SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom-directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease-related organ dysfunction; interferon-α (±corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator-release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib-sensitive KIT mutation or in KITD816-unmutated patients. Treatment of SM-AHNMD is governed primarily by the non-MC neoplasm; hydroxyurea has modest utility in this setting. INVESTIGATIONAL DRUGS Dasatinib's in vitro anti-KITD816V activity has not translated into significant therapeutic activity in most SM patients. In contrast, preliminary data suggest that Midostaurin may produce significant decreases in MC burden in some patients.
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Affiliation(s)
- Animesh Pardanani
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
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Moura DS, Sultan S, Georgin-Lavialle S, Pillet N, Montestruc F, Gineste P, Barete S, Damaj G, Moussy A, Lortholary O, Hermine O. Depression in patients with mastocytosis: prevalence, features and effects of masitinib therapy. PLoS One 2011; 6:e26375. [PMID: 22031830 PMCID: PMC3198767 DOI: 10.1371/journal.pone.0026375] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2011] [Accepted: 09/26/2011] [Indexed: 12/16/2022] Open
Abstract
Depression in patients with mastocytosis is often reported but its prevalence and characteristics are not precisely described. In addition, the impact of therapies targeting mast cells proliferation, differentiation and degranulation on psychic symptoms of depression have never been investigated. Our objective was to determine the prevalence and to describe features of depression in a large cohort of mastocytosis patients (n = 288) and to investigate the therapeutic impact of the protein kinase inhibitor masitinib in depression symptoms. The description of depression was based on the analysis of a database with Hamilton scores using Principal Component Analysis (PCA). Efficacy of masitinib therapy was evaluated using non parametric Wilcoxon test for paired data within a three months period (n = 35). Our results show that patients with indolent mastocytosis present an elevated prevalence of depression (64%). Depression was moderate in 56% but severe in 8% of cases. Core symptoms (such as psychic anxiety, depressed mood, work and interests) characterized depression in mastocytosis patients. Masitinib therapy was associated with significant improvement (67% of the cases) of overall depression, with 75% of recovery cases. Global Quality of Life slightly improved after masitinib therapy and did not predicted depression improvement. In conclusion, depression is very frequent in mastocytosis patients and masitinib therapy is associated with the reduction its psychic experiences. We conclude that depression in mastocytosis may originate from processes related to mast cells activation. Masitinib could therefore be a useful treatment for mastocytosis patients with depression and anxiety symptoms.
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Affiliation(s)
- Daniela Silva Moura
- Université Paris Descartes, Sorbonne, Paris Cité, Service d'hématologie, Centre de référence des mastocytoses, Hôpital Necker Enfants malades, Paris, France
- Université Paris Descartes, Sorbonne, Paris Cité, Laboratoire de Psychopathologie et Processus de Santé EA 4057, IUPDP Institut de Psychologie, Paris, France
| | - Serge Sultan
- Université Paris Descartes, Sorbonne, Paris Cité, Laboratoire de Psychopathologie et Processus de Santé EA 4057, IUPDP Institut de Psychologie, Paris, France
- Université de Montréal, Centre de Recherche du CHU Sainte-Justine, Montréal, Canada
| | - Sophie Georgin-Lavialle
- Université Paris Descartes, Sorbonne, Paris Cité, Service d'hématologie, Centre de référence des mastocytoses, Hôpital Necker Enfants malades, Paris, France
- CNRS UMR 8147, Université Paris Descartes, Sorbonne, Paris Cité, Hôpital Necker-Enfants malades, Paris, France
| | | | | | | | - Stéphane Barete
- Département de dermatologie, Centre de référence des mastocytoses, Hôpital Tenon, Université Pierre et Marie Curie, Paris, France
| | - Gandhi Damaj
- Service d'hématologie, CHU d'Amiens, Université Jules–Vernes Picardie, Amiens, France
| | - Alain Moussy
- AB Science, S.A., Paris, France
- Association Française pour les initiatives et la recherche sur les mastocytes et les mastocytoses (AFIRMM), Paris, France
| | - Olivier Lortholary
- Université Paris Descartes, Sorbonne, Paris Cité, Service de maladies infectieuses et tropicales, Centre de référence des mastocytoses, Hôpital Necker Enfants malades, Paris, France
| | - Olivier Hermine
- Université Paris Descartes, Sorbonne, Paris Cité, Service d'hématologie, Centre de référence des mastocytoses, Hôpital Necker Enfants malades, Paris, France
- CNRS UMR 8147, Université Paris Descartes, Sorbonne, Paris Cité, Hôpital Necker-Enfants malades, Paris, France
- AB Science, S.A., Paris, France
- Association Française pour les initiatives et la recherche sur les mastocytes et les mastocytoses (AFIRMM), Paris, France
- * E-mail:
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Elvevi A, Grifoni F, Branchi F, Gianelli U, Conte D. Severe chronic diarrhea and maculopapular rash: A case report. World J Gastroenterol 2011; 17:3948-52. [PMID: 22025884 PMCID: PMC3198025 DOI: 10.3748/wjg.v17.i34.3948] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2010] [Revised: 02/26/2011] [Accepted: 03/05/2011] [Indexed: 02/06/2023] Open
Abstract
Systemic mastocytosis (SM) is a heterogeneous disease of the bone marrow characterized by abnormal growth, accumulation and activation of clonal mast cells (MCs). We report a case of SM with multi-organ involvement. A 30-year-old man presented with diarrhea, flushing, maculopapular rash with itching and weight loss. The upper and lower gastrointestinal endoscopies showed macroscopic involvement of stomach and duodenum; mucosal samples from stomach, duodenum, colon and distal ileum showed mucosal infiltration by large, spindle-shaped MCs with abnormal surface molecule expression (CD2 and CD25), a picture fully consistent with SM, according to the World Health Organization diagnostic criteria. A computed tomography scan showed diffuse lymphadenopathy, hepatosplenomegaly and diffuse small bowel involvement. Bone marrow aspirate and biopsy were diagnostic for SM; serum tryptase levels were increased (209 ng/mL, normal values < 20 ng/mL). The conclusive diagnosis was smouldering SM. There were no therapeutic indications except for treatment of symptoms. The patient was strictly followed up because of the risk of aggressive evolution.
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Arock M, Valent P. Pathogenesis, classification and treatment of mastocytosis: state of the art in 2010 and future perspectives. Expert Rev Hematol 2011; 3:497-516. [PMID: 21083038 DOI: 10.1586/ehm.10.42] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Mastocytosis is a myeloid neoplasm characterized by abnormal accumulation and frequent activation of mast cells (MCs) in various organs. Organ systems typically involved are the bone marrow, skin, liver and gastrointestinal tract. In most adult patients, the systemic form of mastocytosis (SM) is diagnosed, which includes an indolent subvariant, an aggressive subvariant and a leukemic subvariant, also termed MC leukemia. Whereas in pediatric mastocytosis, which is usually confined to the skin, a number of different KIT mutations and other defects may be detected, the KIT mutation D816V is detectable in most (adult) patients with SM. In a subset of these patients, additional oncogenic factors may lead to enhanced survival and growth of MCs and, thus, to advanced SM. Other factors may lead to MC activation, with consecutive anaphylactic reactions that can be severe or even fatal. Treatment of SM usually focuses on symptom relief by histamine receptor antagonists and other supportive therapy. However, in aggressive and leukemic variants, cytoreductive and targeted drugs must be applied. Unfortunately, the prognosis in these patients remains poor, even when treated with novel KIT-targeting agents, polychemotherapy or stem cell transplantation. This article provides a summary of our knowledge on the pathogenesis and on treatment options in SM.
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Affiliation(s)
- Michel Arock
- Laboratoire de Biologie et Pharmacologie Appliquée, CNRS UMR 8113, Ecole Normale Supérieure de Cachan, 61, Ave du Président Wilson, 94235 Cachan Cedex, France.
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28
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Pardanani A. Systemic mastocytosis in adults: 2011 update on diagnosis, risk stratification, and management. Am J Hematol 2011; 86:362-71. [PMID: 21442641 DOI: 10.1002/ajh.21982] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
DISEASE OVERVIEW Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extracutaneous organs. DIAGNOSIS The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. RISK STRATIFICATION The prognostic relevance of the 2008 World Health Organization (WHO) classification of SM has recently been confirmed. Classification of SM patients into indolent (SM), aggressive SM (ASM), SM associated with a clonal non-MC lineage disease (SM-AHNMD), and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis. RISK-ADAPTED THERAPY SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom-directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease-related organ dysfunction; interferon-α (±corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator-release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib-sensitive KIT mutation or in KITD816-unmutated patients. Treatment of SM-AHNMD is governed primarily by the non-MC neoplasm; hydroxyurea has modest utility in this setting. Dasatinib's in vitro anti- KITD816V activity has not translated into significant therapeutic activity in most SM patients. In contrast, preliminary data suggest that Midostaurin may produce significant decreases in MC burden in some patients.
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Affiliation(s)
- Animesh Pardanani
- Department of Medicine, Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
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Recent advances in mastocytosis and neoplasms of probable monocytic/dendritic cell lineage. ACTA ACUST UNITED AC 2010. [DOI: 10.1016/j.mpdhp.2009.12.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Krauth MT, Mirkina I, Herrmann H, Baumgartner C, Kneidinger M, Valent P. Midostaurin (PKC412) inhibits immunoglobulin E-dependent activation and mediator release in human blood basophils and mast cells. Clin Exp Allergy 2009; 39:1711-20. [PMID: 19860818 DOI: 10.1111/j.1365-2222.2009.03353.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND KIT tyrosine kinase inhibitors (TKI), such as nilotinib or midostaurin (PKC412), are increasingly used in clinical trials to counteract neoplastic cell growth in patients with aggressive mast cell (MC) disorders. However, these patients suffer not only from MC infiltration and consecutive organ damage but also from MC mediator-related symptoms. METHODS We examined the effects of three KIT TKI, imatinib, nilotinib, and midostaurin, on IgE-dependent mediator release in normal human blood basophils and cultured cord blood cell-derived MC, and on spontaneous histamine secretion in the MC leukaemia cell line HMC-1 and the basophil cell line KU812. RESULTS The multi-kinase inhibitor midostaurin that interacts with KIT and protein kinase C was found to counteract anti-IgE-induced mediator release in blood basophils and cultured cord blood cell-derived MC in all samples examined. By contrast, no effects of imatinib or nilotinib on histamine secretion in basophils or MC were found. The effects of midostaurin on histamine release were dose-dependent and occurred at pharmacologic concentrations (IC(50) 10-100 nm). Midostaurin was also found to inhibit the IgE-dependent up-regulation of CD63 on cultured cord blood cell-derived human MC, but did not inhibit IgE-dependent up-regulation of CD63 or CD203c in human blood basophils. CONCLUSION Midostaurin may be a beneficial drug in aggressive systemic mastocytosis not only because of its growth-inhibitory effects but also because of its additional effects on activation and mediator release in MC and basophils.
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Affiliation(s)
- M-T Krauth
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
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31
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Wyndaele JJ, Van Dyck J, Toussaint N. Cystoscopy and bladder biopsies in patients with bladder pain syndrome carried out following ESSIC guidelines. ACTA ACUST UNITED AC 2009; 43:471-5. [DOI: 10.3109/00365590903199007] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Affiliation(s)
- Jean-Jacques Wyndaele
- Department of Urology, Faculty of Medicine, University Antwerp and University Hospital, Antwerp, Belgium
| | - Johan Van Dyck
- Department of Urology, Faculty of Medicine, University Antwerp and University Hospital, Antwerp, Belgium
| | - Nele Toussaint
- Department of Urology, Faculty of Medicine, University Antwerp and University Hospital, Antwerp, Belgium
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32
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Horny HP. Mastocytosis: an unusual clonal disorder of bone marrow-derived hematopoietic progenitor cells. Am J Clin Pathol 2009; 132:438-47. [PMID: 19687320 DOI: 10.1309/ajcppxhmn5cjoxhz] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Mastocytosis, an unusual disorder of bone marrow-derived, clonally transformed hematopoietic progenitor cells, exhibits a broad spectrum of clinical and morphologic features ranging from a self-limiting benign disorder (ie, juvenile cutaneous mastocytosis) to highly aggressive neoplasms like mast cell leukemia. Principally, mastocytosis should be divided in 2 main subentities: cutaneous mastocytosis and systemic mastocytosis mainly involving the bone marrow. Mastocytosis is a morphologic diagnosis and should not be diagnosed on the basis of clinical findings alone. Pathologists need to be aware of the disease and its mimickers. Application of the defined diagnostic criteria can confirm or exclude mastocytosis in most cases. Use of antibodies against tryptase, CD117 (KIT), and CD25 is recommended in every suspected case. Because most cases of systemic mastocytosis show a very low degree of infiltration of the bone marrow, antitryptase and anti-CD117 are of major importance for screening and quantification of mast cells, in particular to detect even small compact infiltrates as the only major diagnostic criterion for mastocytosis. Expression of CD25 on mast cells is defined as a minor diagnostic criterion and is usually seen only in mastocytosis but not in reactive states of mast cell hyperplasia.
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Spontaneous extracutaneous systemic mastocytosis in a cynomolgus macaque (Macaca fascicularis). ACTA ACUST UNITED AC 2009; 62:375-80. [PMID: 19545986 DOI: 10.1016/j.etp.2009.05.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2009] [Revised: 05/14/2009] [Accepted: 05/17/2009] [Indexed: 11/23/2022]
Abstract
A uniform cell population of proliferating mast cells with poor cytoplasmic granularity and a few eosinophilic infiltrates was observed in hepatic portal tracts and the cecal submucosa of an adult male cynomolgus macaque (Macaca fascicularis) that was part of a drug safety assessment toxicity study. The proliferating mast cells were positive for Giemsa and toluidine blue staining and had strong immunoreactivity for mast cell tryptase and CD68. Considering size, morphology, immunoreactivity, and distribution of the lesions a benign proliferative disorder of connective tissue mast cells was diagnosed comparable to that seen in indolent systemic mastocytosis in humans, but lacking associated skin lesions. The finding of visceral mast cell proliferation has to be included in the spontaneous background pathology spectrum of cynomolgus macaques used in toxicological studies.
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Patruno R, Arpaia N, Gadaleta CD, Passantino L, Zizzo N, Misino A, Lucarelli NM, Catino A, Valerio P, Ribatti D, Ranieri G. VEGF concentration from plasma-activated platelets rich correlates with microvascular density and grading in canine mast cell tumour spontaneous model. J Cell Mol Med 2008; 13:555-61. [PMID: 18429933 PMCID: PMC3822515 DOI: 10.1111/j.1582-4934.2008.00355.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Canine cutaneous mast cell tumour (CMCT) is a common cutaneous tumour in dog, with a higher incidence than in human. CMCT is classified in three subgroups, well and intermediately differentiated (G1 and G2), corresponding to a benign disease, and poorly differentiated (G3), corresponding to a malignant disease, which metastasize to lymph nodes, liver, spleen and bone marrow. In this study, we have evaluated serum (S), platelet-poor plasma (P-PP), plasma-activated platelet rich (P-APR) and cytosol vascular endothelial growth factor (VEGF) concentrations, microvascular density (MVD) and mast cell density (MCD) in a series of 86 CMCTs and we have correlated these parameters with each other, by means of ELISA detection of VEGF and immunohistochemistry. Results show that VEGF level from cytosol P-APR and MVD were significantly higher in G3 CMCTs as compared to G1 or G2 subgroups. Moreover, a significantly strong correlation among VEGF levels from P-PAR and cytosol, MVD and MCD was found in G3 subgroup. Because VEGF levels from P-APR well correlated with MVD and malignancy grade in CMCT, we suggest that VEGF might be secreted from MCs and it may be a suitable surrogate inter-species angiogenetic markers of tumour progression in CMCT. Finally, CMCT seems to be a useful model to study the role of MCs in tumour angiogenesis and inhibition of MCs degranulation or activation might be a new anti-angiogenic strategy worthy to further investigations.
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Affiliation(s)
- R Patruno
- Department of Animal Health and Well-Being, University of Bari Veterinary Medical School, Bari, Italy
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35
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Metz M, Brockow K, Metcalfe DD, Galli SJ. Mast cells, basophils and mastocytosis. Clin Immunol 2008. [DOI: 10.1016/b978-0-323-04404-2.10022-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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36
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37
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Shields HM, Shaffer K, O'farrell RP, Travers R, Hayward JN, Becker LS, Lauwers GY. Gastrointestinal manifestations of dermatologic disorders. Clin Gastroenterol Hepatol 2007; 5:1010-7; quiz 1005-6. [PMID: 17825768 DOI: 10.1016/j.cgh.2007.05.018] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The skin and the gastrointestinal tract may be affected concurrently by the same diseases. Pathogenetically, these conditions may be primarily dermatologic diseases involving the gastrointestinal (GI) tract or systemic diseases involving the skin, GI tract, and liver simultaneously. The correct diagnosis of such conditions relies on the ability of the gastroenterologist to recognize the underlying dermatologic disorder. The goal of this clinical review article is to increase gastroenterologists' awareness and understanding of some of these conditions. Case vignettes are presented and the relevant literature reviewed for epidermolysis bullosa, mastocytosis, hereditary hemorrhagic telangiectasia, and melanoma. This review focuses on increasing gastroenterologists' ability to recognize, diagnose, comprehend, and manage patients with these dermatologic conditions who have GI manifestations. Advances in molecular genetics that provide insight into the underlying pathophysiology and histopathology of these lesions are highlighted.
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Affiliation(s)
- Helen M Shields
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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38
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Patnaik MM, Rindos M, Kouides PA, Tefferi A, Pardanani A. Systemic mastocytosis: a concise clinical and laboratory review. Arch Pathol Lab Med 2007; 131:784-91. [PMID: 17488167 DOI: 10.5858/2007-131-784-smacca] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2006] [Indexed: 11/06/2022]
Abstract
CONTEXT Systemic mastocytosis is characterized by abnormal growth and accumulation of neoplastic mast cells in various organs. The clinical presentation is varied and may include skin rash, symptoms related to release of mast cell mediators, and/or organopathy from involvement of bone, liver, spleen, bowel, or bone marrow. OBJECTIVE To concisely review pathogenesis, disease classification, clinical features, diagnosis, and treatment of mast cell disorders. DATA SOURCES Pertinent literature emerging during the last 20 years in the field of mast cell disorders. CONCLUSIONS The cornerstone of diagnosis is careful bone marrow histologic examination with appropriate immunohistochemical studies. Ancillary tests such as mast cell immunophenotyping, cytogenetic/molecular studies, and serum tryptase levels assist in confirming the diagnosis. Patients with cutaneous disease or with low systemic mast cell burden are generally managed symptomatically. In the patients requiring mast cell cytoreductive therapy, treatment decisions are increasingly being guided by results of molecular studies. Most patients carry the kit D816V mutation and are predicted to be resistant to imatinib mesylate (Gleevec) therapy. In contrast, patients carrying the FIP1L1-PDGFRA mutation achieve complete responses with low-dose imatinib therapy. Other therapeutic options include use of interferon-alpha, chemotherapy (2-chlorodeoxyadenosine), or novel small molecule tyrosine kinase inhibitors currently in clinical trials.
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Affiliation(s)
- Mrinal M Patnaik
- Department of Medicine, University of Minnesota, Minneapolis, USA
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Sundram UN, Natkunam Y. Mast cell tryptase and microphthalmia transcription factor effectively discriminate cutaneous mast cell disease from myeloid leukemia cutis. J Cutan Pathol 2007; 34:289-95. [PMID: 17381798 DOI: 10.1111/j.1600-0560.2006.00602.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND Cutaneous mast cell disorders are uncommon, but a subset, especially mastocytoma and mast cell leukemia, can histologically mimic myeloid leukemia cutis. Our objective was to employ a panel of cytochemical and immunohistochemical markers to determine which ones would be most useful in separating these two entities. METHODS We stained 17 cases of cutaneous mast cell disease and 20 cases of myeloid leukemia cutis with Giemsa, toluidine blue, or pinacyanol erythrosinate (PE), as well as with antibodies against mast cell tryptase, microphthalmia transcription factor (MiTF), CD117 (c-kit), myeloperoxidase, CD43, CD25, CD2, and CD68. RESULTS Mast cell tryptase and MiTF emerged as highly sensitive and specific markers for mast cell disease in this context, as both antibodies stained all cases of mast cell diseases but none of myeloid leukemia cutis. Although CD117 stained all cases of mast cell disease, it also stained 2 of 18 cases of myeloid leukemia cutis. PE appeared to be specific for mast cell disease, as 11 of 12 cases stained with this marker, compared with 0 of 18 cases of myeloid leukemia cutis. CONCLUSIONS Our results show that mast cell tryptase and MiTF are equally effective in distinguishing mast cell disease from myeloid leukemia cutis.
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Affiliation(s)
- Uma N Sundram
- Department of Pathology, Stanford University Medical Center, Stanford, CA 94305, USA.
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40
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Proelss J, Wenzel J, Ko Y, Bieber T, Bauer R. Tryptase detection in bone-marrow blood: a new diagnostic tool in systemic mastocytosis. J Am Acad Dermatol 2006; 56:453-7. [PMID: 17317486 DOI: 10.1016/j.jaad.2006.09.020] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2006] [Revised: 09/04/2006] [Accepted: 09/14/2006] [Indexed: 01/08/2023]
Abstract
BACKGROUND The condition mastocytosis includes a heterogenous group of disorders that are characterized by abnormal growth and accumulation of mast cells. The detection of serum tryptase, an essential mast cell enzyme, is a widely used tool in the diagnosis of mastocytosis. The diagnosis of systemic mastocytosis is substantially based on the histologic examination of bone-marrow biopsy specimens. OBJECTIVE We hypothesized that the detection of tryptase in bone-marrow blood might provide additional, more sensitive information on the bone-marrow involvement of patients with mastocytosis. METHODS Serum tryptase was monitored in patients with cutaneous symptoms (n = 17), patients with extracutaneous symptoms (n = 16), and healthy control subjects (n = 359). Bone-marrow biopsy specimens of patients with systemic mastocytosis (n = 7) and control subjects (n = 7) were investigated histologically and bone-marrow blood of these individuals was analyzed on the tryptase levels. RESULTS We could detect for the first time significantly elevated tryptase levels in bone-marrow blood of patients with systemic mastocytosis. Secondarily we could present a clear correlation between the level of serum tryptase and the clinical symptoms of mastocytosis. LIMITATIONS With the present study, we establish a new diagnostic tool for systemic mastocytosis. Unfortunately, we can only present a limited number of cases, since systemic mastocytosis is a rare disease involving few patients. CONCLUSION Our results indicate that the measurement of tryptase in bone-marrow blood is a new, sensitive marker of the mast cell burden in bone marrow of patients with systemic mastocytosis.
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Affiliation(s)
- Julia Proelss
- Department of Dermatology, University of Bonn, Bonn, Germany.
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Horny HP, Sotlar K, Stellmacher F, Krokowski M, Agis H, Schwartz LB, Valent P. The tryptase positive compact round cell infiltrate of the bone marrow (TROCI-BM): a novel histopathological finding requiring the application of lineage specific markers. J Clin Pathol 2006; 59:298-302. [PMID: 16505282 PMCID: PMC1860329 DOI: 10.1136/jcp.2005.028738] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
AIMS Compact tryptase-positive round cell infiltrates of the bone marrow (TROCI-BM) are very rare histopathological findings and may pose challenging problems with regard to the cell type involved (either mast cells or basophilic granulocytes) and the exact diagnosis. METHODS A selected panel of immunohistochemical markers against mast cell and basophil related antigens, including CD25, CD34, CD117/Kit, and the 2D7 antigen (which is found only in basophilic granulocytes) on a total of 410 routinely processed bone marrow biopsy specimens (including 88 cases of systemic mastocytosis (SM), 20 cases of chronic myeloid leukaemia (CML), 92 cases of myeloid neoplasms other than CML, and 210 controls with normal/reactive bone marrows). RESULTS In total, 17 cases with TROCI-BM could be identified: 11 SM (including two cases of well-differentiated SM and two mast cell leukaemias; MCL), 2 myelomastocytic leukaemia (MML), 2 CML with excess of basophils (secondary basophilic leukaemia (CMLba)), and 2 tryptase positive acute myeloid leukaemia (AML). Regarding the cell types involved, TROCI-BM cells were found to express CD117/Kit in all cases of SM and MCL. In MML and tryptase postitive AML, TROCI-BM cells were found to coexpress CD34 and Kit. The basophil specific antigen 2D7 was only detected in CD34/Kit negative TROCI-BM cells in two patients with CMLba. The activating point mutation D816V was detected in 8/11 patients with SM but not in any of the other haematological malignancies. CONCLUSIONS In summary, a total of six rare myeloid neoplasms may present with a novel immunohistochemical phenomenon tentatively termed TROCI-BM.
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Affiliation(s)
- H-P Horny
- University of Lübeck, Institute of Pathology, Lübeck, Germany.
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42
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Samorapoompichit P, Schernthaner GH, Worda C, Wimazal F, Krauth MT, Sperr WR, Valent P. Evaluation of neoplastic human mast cells by tryptase-immunoelectron microscopy. Histopathology 2006; 48:247-57. [PMID: 16430471 DOI: 10.1111/j.1365-2559.2005.02314.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
AIMS To analyse and characterize the ultrastructural morphology of normal tissue mast cells (MC) and neoplastic bone marrow MC. METHODS We have examined the ultrastructure and cytomorphological features of MC derived from cord blood cells, neoplastic bone marrow MC in patients with systemic mastocytosis (SM, n = 4), myelomastocytic leukaemia (MML, n = 2), mast cell leukaemia (MCL, n = 2) and tryptase-positive acute myeloid leukaemia (AML, n = 4). RESULTS Based on their ultrastructure and morphology, four distinct cell types could be delineated: (i) mature well-granulated tissue MC exhibiting a round central nucleus; (ii) atypical MC type I with oval nuclei, hypogranulated cytoplasm, and prominent surface projections; (iii) immature atypical MC with bi- or polylobed nuclei (atypical MC type II = promastocytes); and (iv) metachromatic blasts. Type I atypical MC were detected in a patient with indolent SM, whereas type II MC and metachromatic blasts were primarily found in MML, MCL and tryptase-positive AML. In all samples examined, the identity of MC could be reconfirmed by immunoelectron microscopy, irrespective of the stage of cell maturation or the disease variant, all types of MC contained tryptase in their cytoplasmic granules. CONCLUSION Immunoelectron microscopy may be a helpful approach in confirming the identity of neoplastic MC in myeloid neoplasms.
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MESH Headings
- Adult
- Aged
- Cell Nucleus/ultrastructure
- Cytoplasm/enzymology
- Cytoplasm/ultrastructure
- Female
- Fetal Blood/cytology
- Humans
- Leukemia, Mast-Cell/enzymology
- Leukemia, Mast-Cell/pathology
- Leukemia, Myeloid/enzymology
- Leukemia, Myeloid/pathology
- Leukemia, Myelomonocytic, Acute/enzymology
- Leukemia, Myelomonocytic, Acute/pathology
- Male
- Mast Cells/enzymology
- Mast Cells/pathology
- Mast Cells/ultrastructure
- Mastocytosis, Systemic/enzymology
- Mastocytosis, Systemic/pathology
- Microscopy, Electron
- Microscopy, Immunoelectron
- Middle Aged
- Serine Endopeptidases/analysis
- Tryptases
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Affiliation(s)
- P Samorapoompichit
- Centre of Anatomy and Cell Biology, Institute of Histology & Embryology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria
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Abstract
Systemic mastocytosis is a fascinating disease with diverse clinical features. There have been numerous advances in understanding the basis of clinical manifestations of this disease and of its molecular pathogenesis in the last several decades. The development of methods to study mast cell biology using cell culture and murine models has proven invaluable in this regard. Clarification of the roles of mast cells in various biological processes has expanded our understanding of their importance in innate immunity, as well as allergy. New diagnostic methods have allowed the design of detailed criteria to assist in distinguishing reactive mast cell hyperplasia from systemic mastocytosis. Variants and subvariants of systemic mastocytosis have been defined to assist in determining prognosis and in management of the disease. Elucidation of the roles of the Kit receptor tyrosine kinase and signal transduction pathway activation has contributed to development of potential targeted therapeutic approaches that may prove useful in the future.
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Affiliation(s)
- Jamie Robyn
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
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Agis H, Sotlar K, Valent P, Horny HP. Ph-Chromosome-positive chronic myeloid leukemia with associated bone marrow mastocytosis. Leuk Res 2005; 29:1227-32. [PMID: 16111540 DOI: 10.1016/j.leukres.2005.04.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2004] [Revised: 04/01/2005] [Accepted: 04/03/2005] [Indexed: 01/08/2023]
Abstract
The concurrent development of chronic myeloid (CML) or myelomonocytic (CMML) leukemia in patients with systemic mastocytosis (SM) is a well recognized phenomenon. Although the leukemia often resembles CML in morphological and in clinical terms, a Ph-Chromosome-positive variant has not been reported in SM so far. We here describe a 43-year-old female patient with typical Ph-Chromosome-positive CML in whom a co-existing bone marrow mastocytosis, a special subvariant of SM, was diagnosed. RT-PCR analysis revealed the typical p210 kDa form of BCR/ABL in leukemic cells. The diagnosis SM was based on the typical focal aggregates of spindle-shaped mast cells (MC) in the bone marrow, expression of CD25 in MC, and the c-kit mutation D816V, which was detectable in microdissected bone marrow MC, but not in microdissected leukemic cells, suggesting the presence of two different (sub)clones of neoplastic cells. Therapy with the BCR/ABL-targeting drug Imatinib (STI571) resulted in complete cytogenetic remission of CML. Together, our case provides further evidence for the biologic diversity of leukemias that may occur in patients with SM. The exact knowledge of the pathology and target-profile of the associated leukemias in SM have important therapeutic implications.
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MESH Headings
- Adult
- Benzamides
- Bone Marrow/metabolism
- Bone Marrow/pathology
- Female
- Fusion Proteins, bcr-abl/physiology
- Humans
- Imatinib Mesylate
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Mastocytosis, Systemic/drug therapy
- Mastocytosis, Systemic/etiology
- Piperazines/therapeutic use
- Proto-Oncogene Proteins c-kit/metabolism
- Pyrimidines/therapeutic use
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Affiliation(s)
- Hermine Agis
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria
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Terzi A, Sağlam EA, Uner AH. A 55-year-old man with erythematous urticarial plaques, hepatosplenomegaly, and bicytopenia. Arch Pathol Lab Med 2005; 129:e151-2. [PMID: 15913445 DOI: 10.5858/2005-129-e151-aymweu] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Aysen Terzi
- Department of Pathology, Hacettepe University, School of Medicine, Ankara, Turkey
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Pardanani A. Systemic mastocytosis: bone marrow pathology, classification, and current therapies. Acta Haematol 2005; 114:41-51. [PMID: 15995324 DOI: 10.1159/000085561] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Mast cell disease (MCD) is characterized by the abnormal growth and accumulation of neoplastic mast cells (MC) in one or more organs. The diagnosis of systemic MCD is most commonly established by a thorough histological and immunohistochemical examination of a bone marrow (BM) trephine specimen. In cases with pathognomonic perivascular and -trabecular aggregates of morphologically atypical MC and significant BM involvement, the diagnosis may be relatively straightforward. In contrast, when a sparse, loose pattern of MC infiltration predominates, or when MCs are obscured by an associated non-MC hematological neoplasm, a high index of suspicion and use of adjunctive tests, including special stains, such as tryptase and CD25, may be necessary to reach a diagnosis. The updated classification for MCD clarifies the clinical and pathological criteria for categorizing patients into relatively discrete subgroups. Some cases, however, such those with Fip1-like-1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA)(+) clonal eosinophilia associated with elevated serum tryptase levels, with features that overlap MCD and chronic eosinophilic leukemia, may not be easy to categorize on the basis of this classification. There is no standard therapy for MCD and treatment has to be tailored to the needs of the individual patient. MC-cytoreductive therapies, such as interferon-alpha and chemotherapy, are generally reserved for patients with progressive disease and organopathy. A subset of MCD patients with associated eosinophilia who carry the FIP1L1-PDGFRA oncogene will achieve complete clinical, histological, and molecular remissions with imatinib mesylate therapy, in contrast to those with c-kit D816V mutations. The BM pathology, consensus classification, and current therapies for MCD are further discussed in this article.
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Affiliation(s)
- A Pardanani
- Divisions of Hematology and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
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Sotlar K, Horny HP, Simonitsch I, Krokowski M, Aichberger KJ, Mayerhofer M, Printz D, Fritsch G, Valent P. CD25 Indicates the Neoplastic Phenotype of Mast Cells. Am J Surg Pathol 2004; 28:1319-25. [PMID: 15371947 DOI: 10.1097/01.pas.0000138181.89743.7b] [Citation(s) in RCA: 135] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The diagnosis of systemic mastocytosis (SM) is based primarily on the histologic and immunohistochemical evaluation of a bone marrow trephine biopsy specimen. Although mast cell (MC) specific antigens like tryptase and chymase are detectable in routinely processed tissue, no immunohistochemical markers that can be used to discriminate between normal and neoplastic MCs are yet available. We have investigated the diagnostic value of an antibody against CD25 for the immunohistochemical detection of MCs in bone marrow sections in 73 patients with SM and 75 control cases (reactive marrow, n = 54; myelogenous neoplasms, n = 21) and correlated the results with the presence of c-kit mutations. While MCs in almost all patients with SM (72 of 73) expressed CD25, none of the control samples contained CD25-positive MCs. Irrespective of the SM subtype, most of neoplastic MCs expressed CD25. In 3 patients with advanced MC disease, pure populations of neoplastic MCs were obtained and found to express CD25 mRNA by RT-PCR analysis. In addition, all patients with CD25-positive MCs contained c-kit mutations, while all control cases exhibited wild type c-kit. CD25 therefore appears to be a reliable immunohistochemical marker for the discrimination of neoplastic from normal/reactive MCs, with potential as a diagnostic tool in SM.
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Affiliation(s)
- Karl Sotlar
- Institute of Pathology, University of Tübingen, Tübingen, Germany
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Valent P, Sperr WR, Schwartz LB, Horny HP. Diagnosis and classification of mast cell proliferative disorders: delineation from immunologic diseases and non–mast cell hematopoietic neoplasms. J Allergy Clin Immunol 2004; 114:3-11; quiz 12. [PMID: 15241337 DOI: 10.1016/j.jaci.2004.02.045] [Citation(s) in RCA: 96] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
In mast cell (MC) disorders (mastocytosis), clinical symptoms are caused by the release of chemical mediators from MCs, the pathologic infiltration of neoplastic MCs in tissues, or both. Cutaneous mastocytosis is a benign disease in which MC infiltration is confined to the skin. In pediatric cases cutaneous mastocytosis might regress spontaneously. Systemic mastocytosis (SM) is more frequently diagnosed in adults and is a persistent (clonal) disease of bone marrow-derived myelomastocytic progenitors. The somatic c-kit mutation D816V is found in the majority of such patients. The natural clinical course in SM is variable. Whereas most patients remain at the indolent stage for many years, some have aggressive SM (ASM) at diagnosis. Other patients have an associated clonal hematologic non-MC lineage disease (AHNMD). MC leukemia (MCL) is a rare disease variant characterized by circulating MCs and fatal disease progression. The diagnoses of ASM, SM-AHNMD, and MCL might be confused with a variety of endocrinologic, vascular, or immunologic disorders. It is therefore of particular importance to be aware of the possibility of an underlying (malignant) MC disease in patients with unexplained vascular instability, unexplained (anaphylactoid) shock, idiopathic flushing, diarrhea, headache, and other symptoms that might be mediator related. An important diagnostic clue in such cases is an increased serum tryptase level. The current review provides an overview of mastocytosis and its subvariants and a practical guide that might help to delineate mastocytosis from unrelated systemic disorders.
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Affiliation(s)
- Peter Valent
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria.
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Abstract
Urticaria pigmentosa (UP), resulting from the accumulation of excessive numbers of mast cells in the skin, is the most common form of cutaneous mastocytosis. Observations highlight the diversity of this disease. Clonal expansion of early hematopoietic progenitor cells carrying activating mutations in KIT seems to be the basis of adult-onset UP. New pathogenetic findings are leading to the development of new diagnostic surrogate markers of disease and therapeutic approaches targeting neoplastic mast cells. Promising strategies may arise from an increased understanding about the cause of mastocytosis and the signaling pathways initiated by kit activation.
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Affiliation(s)
- Knut Brockow
- Department of Dermatology and Allergy Biederstein, Technical University Munich, Biedersteiner Strasse, 29 80802 Munich, Germany.
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Valent P, Akin C, Sperr WR, Horny HP, Arock M, Lechner K, Bennett JM, Metcalfe DD. Diagnosis and treatment of systemic mastocytosis: state of the art. Br J Haematol 2003; 122:695-717. [PMID: 12930381 DOI: 10.1046/j.1365-2141.2003.04575.x] [Citation(s) in RCA: 144] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
- Peter Valent
- Department of Internal Medicine I, Division of Haematology, University of Vienna, Austria.
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